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WO2018207099A1 - Traitement du syndrome des ovaires polykystiques - Google Patents

Traitement du syndrome des ovaires polykystiques Download PDF

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Publication number
WO2018207099A1
WO2018207099A1 PCT/IB2018/053199 IB2018053199W WO2018207099A1 WO 2018207099 A1 WO2018207099 A1 WO 2018207099A1 IB 2018053199 W IB2018053199 W IB 2018053199W WO 2018207099 A1 WO2018207099 A1 WO 2018207099A1
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WIPO (PCT)
Prior art keywords
treatment
study
lik066
subject
pcos
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PCT/IB2018/053199
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English (en)
Inventor
William CHUTKOW
Carla KLATTENHOFF
C. Daniel MEYERS
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Novartis AG
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • the present invention relates to pharmaceutical uses of LIK066, their
  • PCOS polycystic ovary syndrome
  • PCOS Polycystic ovary syndrome
  • Insulin resistance is a common feature of PCOS across the weight spectrum, partly reflecting an intrinsic element of resistance with exacerbation by obesity.
  • the insulin resistance appears to be tissue specific primarily affecting skeletal muscle and adipose tissue, but not ovarian and adrenal tissues.
  • the compensatory hyperinsulinism has tissue- selective effects, which include aggravation of hyperandrogenism, primarily by stimulating activity of the cytochrome P450c 17a in the ovary.
  • Hyperinsulinism also acts on the liver to decrease the production of sex hormone binding globulin (SHBG), thus leading to increased circulating levels of free androgens; and possibly at the level of the pituitary gonadotropes, by increasing production of luteinizing hormone (LH), which in turn stimulates ovarian steroidogenesis.
  • SHBG sex hormone binding globulin
  • LH luteinizing hormone
  • Interventions that reduce serum insulin levels such as metformin, insulin-sensitizing thiazolidinediones, and weight loss result in significant improvement of
  • SGLT cotransporter 2 inhibitor approved for T2D
  • PCOS cotransporter
  • metformin or exenatide to evaluate the relationship of insulin resistance, body weight and effects on hyperandrogenemia.
  • hyperinsulinism and hyperandrogenism in PCOS and clinical evidence that lowering insulin levels and/or increasing insulin sensitivity improve hyper androgenism and ovulation in these patients.
  • PCOS type 2 diabetes
  • cardiovascular disease There is no cure for PCOS.
  • Treatment involves management of symptoms by lifestyle modification such as weight loss, cosmetic interventions, pharmacotherapy for hirsutism, menstrual irregularities and infertility treatments.
  • SGLT 1 and 2 Sodium-glucose cotransporters (SGLT) 1 and 2 play an important role in glucose homeostasis with SGLT1 being the primary transporter responsible for absorption of glucose and galactose in the intestine, and SGLT 2 being the primary transporter responsible for renal glucose reabsorption.
  • SGLT2 inhibitors are approved for the treatment of type 2 diabetes, acting primarily by increasing urinary glucose excretion (UGE) and improving glycemic control. Blockade of enteric SGLT1 results in glucose and galactose malabsorption. There are no approved dual inhibitors of SGLT 1 and 2.
  • LIK066 is a highly selective, safe and potent dual SGLT1/2 inhibitor that is in development at Novartis for obesity.
  • the pharmacodynamic effects of LIK066 include increased urinary glucose excretion (UGE), and inhibition of glucose absorption from the gut. Body weight loss has been demonstrated in a phase 2a trial in obesity.
  • LIK066 significantly reduces post-prandial glucose and insulin excursions in healthy volunteers, obese populations and T2D populations. This effect is observed with single dose and is acute, meaning that it is observed on the meal immediately following dosing and not 6 hours later, which suggests a direct lumenal effect on gut SGLT1 inhibition. This effect is also dose dependent, with maximal post-prandial insulin suppression at 50 mg or higher. Fasting insulin and glucose levels are not significantly affected by LIK066. To date, there are no data on the effect of LIK066 on androgen levels.
  • a method for the treatment or prevention of polycystic ovary syndrome (PCOS) in a subject in need of such treatment which comprises administering to said subject a therapeutically effective amount of an a inhibitor of SGLT1 and SGLT2, e.g., LIK066, or a pharmaceutically acceptable salt thereof.
  • PCOS polycystic ovary syndrome
  • the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS.
  • the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS.
  • the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of PCOS.
  • a method for the treatment or prevention of PCOS in a subject with Type 2 Diabetes and/or obesity which comprises administering to said subject a therapeutically effective amount of LIK066, or a pharmaceutically acceptable salt thereof.
  • the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS in a patient with Type 2 diabetes and/or obesity.
  • the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS in a patient with Type 2 diabetes and/or obesity.
  • the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of PCOS in a patient with Type 2 Diabetes and/or obesity.
  • FIG. 1 depicts the study design.
  • FIG. 2 depicts the assessment schedule.
  • FIG. 3 depicts the assessment schedule.
  • FIG. 4 depicts the assessment schedule.
  • FIG. 5 depicts the assessment schedule.
  • the invention is a method for the treatment or prevention of
  • PCOS which comprises administering to said subject a therapeutically effective amount of LIK066, or a pharmaceutically acceptable salt thereof.
  • the invention is the method according to the first embodiment, wherein about 50 mg of LIK066 is administered three times per day ("tid").
  • the invention is the method according to any one of the first or second embodiments, wherein LIK066 is administered just before a meal.
  • the invention is the method according to any one of the previous embodiments, wherein the subject is at least 18 years old.
  • the invention is the method according to any one of the first through third embodiments, wherein the subject is obese, defined as an individual having a Body Mass Index (BMI) ⁇ 22kg/m 2 .
  • BMI Body Mass Index
  • the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS.
  • the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS.
  • the invention is the pharmaceutical composition according to the seventh embodiment, wherein the compositions comprises 50 mg of LIK066.
  • the invention is the pharmaceutical composition according to the seventh or eighth embodiment, wherein the pharmaceutical composition is administered three times per day.
  • the invention is the pharmaceutical composition according to any one of the seventh through ninth embodiments, wherein the subject has a BMI ⁇ 22kg/m 2 .
  • the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of PCOS.
  • the invention is the medicament according to the eleventh embodiment, wherein the compositions comprises 50 mg of LIK066.
  • the invention comprises LIK066 for use in the treatment of PCOS.
  • the invention comprises LIK066 for use in the treatment of PCOS in a subject with T2D, particularly to any individual with an HbA1c between 7.0% and 10.0%.
  • the invention comprises LIK066 for use in the treatment of
  • PCOS in a subject with a BMI ⁇ 22kg/m 2 PCOS in a subject with a BMI ⁇ 22kg/m 2 .
  • the invention is a pharmaceutical unit dose comprising 50 mg of LIK066.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free base/free acid of a compound represented by formula (I) that is not toxic, biologically intolerable, or otherwise biologically undesirable.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Such salts are known in the field (e.g., S.M. Berge, et al, "Pharmaceutical Salts", J. Pharm.
  • LIK066 is an inhibitor of the sodium-glucose co- transporter- 1 (SGLT1) and sodium- glucose co-transporter-2 (S chemical structure:
  • LIK066 has the following lUPAC name: (2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1 ,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol.
  • LIK066 for use in the present invention is either obtained in the free form, as a salt thereof, a co-crystal or as prodrug derivatives thereof.
  • LIK066 including its salts can also be obtained in the form of its hydrates, or include other solvents used for its crystallization. LIK066 may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • LIK066, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
  • the higher oral bioavailability of LIK066 may give rise to the following beneficial effects relating to less bioavailable compounds: (i) an enhanced biological effect may be achieved after oral administration; (ii) an earlier onset of action may be observed following oral administration; (iii) a lower dose may be needed to achieve the same effect; (iv) a higher effect may be achieved by the same dose or (v) a prolonged action may be observed at the same dose.
  • subject typically refers to a human, especially to a human patient diagnosed with PCOS.
  • treatment refers to any type of treatment that imparts a benefit to a subject affected with PCOS.
  • PCOS is a common endocrine disorder among women of reproductive age. PCOS may result in enlarged ovaries, and physically manifest as excess hair growth, acne, obesity or infrequent or prolonged menstrual cycles. PCOS is typically diagnosed via one of two methods: clinical or biochemical hyperandrogenism. Clinical hyperandrogenism is defined as moderate to severe hirsutism with a Ferriman-Gallway score of > 9 AND a free
  • testosterone level that is equal to or > 50% above the ULN (defined below), while
  • biochemical hyperandrogenism is defined as free testosterone level that is equal to or > 75% above the ULN.
  • the appropriate dosage will vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in are indicated to be obtained at a daily dosage of from about 0.01 to about 100 mg/kg body weight, preferably from about 1 to about 30 mg/kg body weight, e.g., 10 mg/kg.
  • An indicated daily dosage is in the range from about 0.1 to about 1000 mg, preferably from about 1 to about 150 mg, conveniently administered, for example, in an oral dose delivered 1-3 times per day. In one embodiment, about 50 of LIK066 is administered three times a day.
  • LIK066 may be administered in any usual manner, e.g., orally, for example in the form of tablets, capsules or drinking solutions; rectally, for example in the form of suppositories; intravenously, for example in the form of injection solutions or suspensions; or transdermal, for example in the form of a patch.
  • the manner of administration is oral administration, for example in the form of a tablet, capsule or drinking solution.
  • the manner of administration is rectal administration, for example in the form of a suppository.
  • the manner of administration is transdermal administration, for example in the form of a patch.
  • the manner of administration is oral administration.
  • compositions comprise LIK066 in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in
  • Unit dosage forms may contain LIK066 in an amount greater than or equal to 2.5mg, for example greater than or equal to 10mg, such as for example greater than or equal to 50mg.
  • Unit dosage forms may also contain LIK066 in an amount of greater than or equal to 2.5mg, 10mg, 40mg, 50mg, 75mg or 100mg or greater than or equal to 150mg or 200mg.
  • Unit dosage forms may contain LIK066 in an amount less than or equal to 100mg, for example less than or equal to 100mg, such as for example less than or equal to 50 mg or for example less than or equal to 10mg or for example less than or equal to 2.5mg.
  • Unit dosage forms may also contain LIK066 in an amount in the range from 1 -100mg, e.g., 1-75mg or 1- 60mg such as 2-55mg.
  • compositions according to the invention are compositions for enteral administration, such as oral or rectal administration; or parenteral administration, such as intramuscular, intravenous, and nasal or transdermal administration, to warmblooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier.
  • the dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • compositions comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
  • Compositions for transdermal administration are described in Remington's Pharmaceutical Sciences 16 th Edition Mack; Sucker, Fuchs and Spieser, Pharmazeutician Technologie, 1 st Edition, Springer.
  • Dosage subject in a time unit e.g., 100 mg once a day, 75 mg twice a day
  • EDC Electronic data capture
  • EDC Electronic Data Capture
  • EDC includes the use of Electronic Case Report Forms (eCRFs) which are used to capture data transcribed from paper source forms used at the point of care.
  • eCRFs Electronic Case Report Forms
  • An epoch is associated with a purpose
  • Epoch (e.g., screening, randomization, treatment, follow-up) which applies across all arms of a study.
  • Source data refers to the initial record, document, or primary location from where
  • Source Data/Document data comes.
  • the data source can be a
  • Study treatment of the required study procedures includes investigational drug(s), control(s) or background therapy
  • a trial participant can be a healthy volunteer
  • a unique number assigned to each subject upon signing the informed consent is the definitive, unique identifier for
  • Approximately 24 subjects are randomized in a 1 :1 ratio to LIK066 or placebo (12 subjects on LIK066; 12 on placebo). Discontinued subjects may be replaced. If more than 2 subjects experience menstrual bleeding during the study, additional subjects may be enrolled to account for those subjects in case they are excluded from the pharmacodynamic analysis set (if ovulation is confirmed based on progesterone assessment). The number of enrolled subjects; excluding replacements, should not exceed 30.
  • the treatment period is 2 weeks; dosing is oral, just before meals, 50 mg of LIK066 or matching placebo t.i.d. for 14 days and only one dose in the morning on Day 15.
  • Each subject participates in a screening period of up to 6 weeks, a baseline period (including an optional overnight stay at the study site), a treatment period of 2 weeks (outpatient visits and one optional overnight stay at end of treatment), and a follow-up period of about 1 week with an end of study visit on
  • a subject's duration of participation in the study is up to a total of 9 weeks inclusive of the 6-week screening window.
  • the baseline visit (Day -1) includes an optional overnight stay (starting Day -2) and an 8- 10 hour overnight fast.
  • Serial blood samples for hormone levels is collected between 6 am and 8 am the following morning (Day -1), followed by the test meal for breakfast (without drug administration) and serial post-prandial blood sampling over a 4 hour period.
  • baseline safety labs must be reviewed by the investigator to ensure eligibility criteria continue to be met and to then enable randomization.
  • the investigator must randomize eligible subjects on, or prior to, Day 1.
  • the site staff must provide subjects with study drug and instructions on drug administration immediately before meals, three times a day.
  • the site staff should inform subjects that they are to avoid high carbohydrate meals in order to minimize Gl discomfort with dosing.
  • a follow-up visit is conducted on Day 8 to check tolerability, safety and compliance. This visit may be conducted either by phone or in person at the site, at the discretion of the investigator.
  • End-of-Study visit will occur on approximately Day 22, for study completion evaluations. This visit may be performed earlier in the case of early termination.
  • the physical examination includes cutaneous manifestations of hyperandrogenism, e.g., hirsutism, acne, androgenic alopecia, as well as acanthosis nigricans and skin tags; baseline measures of body weight, waist circumference, hip circumference and waist/hip ratio.
  • the medical history includes the approximate onset of the last menstrual period and prior history of gestational diabetes.
  • endocrine assessments include total testosterone, free testosterone, LH,
  • FSH FSH, SHBG, estradiol, progesterone, DHEAS, DHEA, androstenedione, insulin and glucose.
  • Safety assessments throughout the study include vital signs, physical examinations, ECGs, standard clinical laboratory evaluations (blood chemistry, hematology, urinalysis), adverse events and serious adverse events.
  • Including a placebo arm also helps for causality evaluation of adverse events in relation to study drug, study procedures and/or underlying disease.
  • Domiciling controls for confounders that influence the circadian rise in testosterone
  • Free testosterone (T) as primary end-point Free T and not total T, is considered to be more sensitive as a diagnostic marker of hyperandrogenism in women with PCOS. Total testosterone has inadequate sensitivity to differentiate between normal and PCOS women. Free T is also the biologically active form of testosterone and, unlike total T, free T may significantly change in response to treatment effects on SHBG.
  • Test meal A standardized breakfast test meal is used to evaluate the post-prandial effect of LIK066 on insulin excursion and enable evaluation of the relationship between effects of LIK066 on insulin and those on androgen levels, in support of the primary hypothesis of this study.
  • the test meal is enriched for carbohydrate in order to stimulate insulin release.
  • the test meal is benchmarked to tests used in other clinical studies with LIK066 in order to enable comparison of treatment effects across studies and
  • ⁇ PK sampling Limited number of PK samples are collected on Day 15 at the time of test meal, in order to evaluate the steady-state PK of LIK066 in subjects with PCOS, and to assist with PKPD analyses or modeling activities.
  • the dosing regimen for LIK066 in this study is 50 mg orally (or matching placebo), t.i.d. before each main meal (Quaque ante cibum, q.a.c.) (before breakfast, lunch and dinner) for 14 days. The last dose is administered on Day 15 morning before the test meal.
  • LIK066 regimens of either 50 mg or 150 mg once a day are approximately ⁇ ED 8 o for maximal urine glucose excretion (UGE), and are predicted to be ⁇ ED 90 for body weight loss, reflecting dual SGLT1 and SGLT2 inhibition At these doses, LIK066 has been shown to reduce post-prandial incremental insulin and plasma glucose in a dose-dependent manner in clinical studies in healthy, obese and T2D subjects.
  • LIK066 on glucose and insulin is observed on the meal that immediately follows dosing, and not significantly with later meals, possibly due to limited lumenal exposure time to LIK066.
  • an LIK066 dose of 150 mg induced acute reduction of post-prandial glucose and insulin but had no apparent effect on a test meal given approximately 6 hours post- dose as reported in the IB.
  • LIK066 will be administered immediately before each of the main meals; breakfast, lunch and dinner, i.e. t.i.d. and q.a.c. to ensure repeated pharmacologic reduction in insulin response per meal.
  • This regimen is expected to induce a more sustained reduction in cumulative insulin levels at least during the daytime.
  • the local gut lumenal exposure to LIK066 has been associated with Gl symptoms, notably diarrhea and flatulence that are temporally related to meal intake with dosing.
  • the daily systemic exposure from the 50 mg t.i.d. regimen in the PCOS population is expected to maintain a ⁇ 10-fold exposure multiple relative to the NOEL AUC threshold for aneugenicity.
  • Rationale for treatment duration A 14 day treatment period is expected to support an effect of LIK066 on androgen levels in this population given the expected magnitude of reduction in overall insulin levels with t.i.d. dosing.
  • a placebo group is included to ensure blinding and to determine the study effect.
  • the study population consists of female patients ( ⁇ 18 years old) with PCOS.
  • Clinical hyperandrogenism is defined as moderate to severe hirsutism with a Ferriman- Gallway score of > 9 AND a free testosterone level that is equal to or > 50% above the ULN.
  • Biochemical hyperandrogenism is defined as free testosterone level that is equal to or > 75% above the ULN.
  • the screening labs for free T can be repeated once for borderline levels; the highest level of free T must be considered for eligibility.
  • the Investigator should obtain two additional readings, so that up to three consecutive assessments are made, following the procedure in the SOM. At least the last reading must be within the ranges provided above in order for the subject to qualify.
  • Postural hypotension is defined as either a > 20 mmHg decrease in systolic or a >10 mmHg decrease in diastolic blood pressure, accompanied by a > 20 bpm increase in heart-rate (from sitting to standing).
  • Non-hormonal contraception methods include:
  • IUD intrauterine device
  • spermicidal foam/gel/film/cream/vaginal suppository spermicidal foam/gel/film/cream/vaginal suppository.
  • UTI Symptomatic genital or urinary tract infection
  • absorption e.g., bariatric surgeries including, Roux-en-Y gastric bypass, sleeve gastrectomy, Nissen fundoplication
  • active gastrointestinal disorders such as irritable bowel syndrome and inflammatory bowel disease.
  • Gl disorder related to malabsorption or that may affect drug or glucose absorption e.g., swallowing disorder, severe Gl motility disorder, chronic diarrhea, glucose/galactose/lactose intolerance
  • hormonal therapy including but not limited to estrogen/progesterone contraceptives, estrogens, androgens, gonadotropin-releasing hormone within 3 months of screening, or progesterone contraceptives within 1 month of screening.
  • Thyroid replacement therapy is allowed; subjects must be on a stable dose for at least 3 months prior to screening.
  • Infertility treatment e.g., letrozole and clomiphene citrate within 1 month of screening
  • CYP3A4/5 Strong inhibitors of CYP3A4/5 including boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole at least 7 days prior to the study treatment.
  • acetaminophen or ibuprofen is acceptable for incidental and limited use.
  • myocardial infarct (Ml), unstable angina, or clinically significant ECG abnormalities at screening 16.
  • Ketoacidosis, lactic acidosis, or hyperosmolar coma within 6 months of screening.
  • Randomized treatment is assigned to individual subjects by way of a randomization number, which will be in the range of 5101-5130.
  • the randomization number is only used to identify which treatment the subjects have been randomized to receive.
  • the Subject number assigned to a subject at screening remains the unique identifier for the subject throughout the study.
  • Replacement randomization numbers will be in the range of 6101-6130. If a subject requires a replacement, the replacement subject will be assigned a randomization number corresponding to the original subject (e.g. , Subject 6103 would replace Subject 5103). Any additional subjects enrolled will use sequential subject numbering.
  • the randomization numbers are generated using the following procedure to ensure that treatment assignment is unbiased and concealed from subjects and investigator staff. Treatment allocation cards (noting the randomization numbers) will be produced by or under the responsibility of Novartis Drug Supply Management using a validated system that automates the random assignment of treatment arms to randomization numbers in the specified ratio.
  • the randomization scheme for subjects will be reviewed and approved by a member of the Randomization Office.
  • the investigator will enter the randomization number on the CRF (eCRF). If more than one study center recruits subjects simultaneously, the CTL or designee will coordinate assigning randomization numbers across sites as described in the SOM.
  • Drug product will be supplied in bulk, so an unblinded pharmacist who is
  • the unblinded field monitors are required to review drug accountability and allocation at site.
  • the unblinded monitors are not provided with a randomization list directly but will be unblinded through review of source documentation compiled by the unblinded pharmacist, which details treatment allocation to individual subjects.
  • the unblinded monitors will also be able to review the treatment allocation cards provided to the unblinded pharmacist.
  • the sample analysts will receive a copy of the randomization schedule (via request to the Randomization Office), to facilitate analysis of the samples.
  • the sample analysts will provide the sample data to the study team under blinded conditions unless otherwise allowed.
  • the study statistician will be able to access the randomization list for interim analyses and is allowed to share unblinded information with the rest of the clinical team as appropriate for internal decision purposes. For example, unblinded summaries and unblinded individual data can be shared with the team for interim analyses. Study programmers and other personnel involved in study data analysis (e.g., biomarker expert) are allowed to access treatment assignment information for the purpose of conducting interim analyses.
  • the clinical trial team is allowed to share unblinded results with other sponsor staff (e.g., decision boards) as required for internal decision making on the study or the project at the time of interim analyses while the study is ongoing.
  • sponsor staff e.g., decision boards
  • Each study site is supplied with study drug in packaging of identical appearance.
  • the study drug packaging has a 2-part label. A unique randomization number is printed on each part of this label which corresponds to one of the treatment arms.
  • Investigator staff identify the study drug package(s) to dispense to the patient by contacting the IRT and obtaining the medication number(s). Immediately before dispensing the package to the patient, investigator staff detach the outer part of the label from the packaging and affix it to the source document (Drug Label Form) for that patient's unique patient number.
  • the investigator must instruct the patient to notify the study site about any new medications he/she takes after the patient was enrolled into the study. All medications, procedures and significant non-drug therapies (including physical therapy and blood transfusions) administered after the patient was enrolled into the study must be recorded in the Concomitant Medications/Surgical and Medical Procedures eCRF. Every effort should be made by the Investigator to keep the dose level of each patient's allowed background heart failure medications stable throughout the entire study duration. However; if the clinical condition of the patient warrants a change in any of these medications, it is allowed at the discretion of the study Investigator. Each concomitant drug must be individually assessed against all exclusion criteria/prohibited medication. If in doubt the investigator should contact the Novartis medical monitor before randomizing a patient or allowing a new medication to be started.
  • Emergency code breaks are only undertaken when it is required to in order to treat the patient safely. Most often, study treatment discontinuation and knowledge of the possible treatment assignments are sufficient to treat a study patient who presents with an emergency condition.
  • Emergency treatment code breaks are performed using the IRT. When the investigator contacts the system to break a treatment code for a patient, he/she must provide the requested patient identifying information and confirm the necessity to break the treatment code for the patient. The investigator then receives receive details of the investigational drug treatment for the specified patient and communication confirming this information. The system automatically informs the Novartis monitor for the site and the Study Team that the code has been broken.
  • the investigator It is the investigator's responsibility to ensure that there is a dependable procedure in place to allow access to the IRT system at any time in case of emergency.
  • the investigator provides the protocol number, the study drug name (if available) and the patient number.
  • oral and written information to the patient is provided on how to contact the investigator ' s backup in cases of emergency, or when the investigator is unavailable, to ensure that un-blinding can be performed at any time. Patients whose treatment has been unmasked must be discontinued from study treatment. Study completion and post-study treatment
  • a patient is considered to have completed the study when the patient has completed the last planned visit (see FIGs 2-5).
  • the study as a whole is considered completed when all randomized subjects have completed the last visit planned in the protocol or have discontinued the study prematurely.
  • the investigator must provide follow-up medical care for all subjects who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
  • Figures 2-5 list all of the study visits and assessments and indicates with an "X" when the assessments are performed. Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely discontinue the study for any reason should be scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit will be performed. At this final visit, all dispensed investigational product should be reconciled and the adverse event and concomitant medications reconciled on the eCRF. Patients will be contacted for safety evaluations during the 30 days following the last administration of study treatment.
  • Demographic and BL characteristics data collected on all randomized patients include: year of birth, age, sex, race, ethnicity, relevant medical history/current medical conditions present before signing informed consent including smoking and alcohol history. Where possible, diagnoses and notable symptoms are recorded. Investigators have the discretion to record abnormal test findings on the medical history eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent form (ICF) signature. Treatment exposure and compliance
  • Compliance is assessed by the investigator and/or study personnel at each visit using pill counts and information provided by the patient. This information is captured in the source documents at each visit. All study treatment dispensed and returned must be recorded in the Drug Accountability Log. The site is also required to complete the
  • Efficacy Pharmacodynamic (PD) samples will be collected at the timepoints defined in the Assessment schedule as set forth in Figs. 2-5. PD samples will be obtained and evaluated in all subjects, including the placebo group. Pharmacodynamic assessments include :
  • Designated investigator staff will enter the data required by the protocol into the Electronic Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. Designated investigator site staff will not be given access to the EDC system until they have been trained. Validation checks for data discrepancies and, by generating appropriate error messages, allow the data to be confirmed or corrected before transfer of the data to Novartis or the CRO working on behalf of Novartis. The Investigator must certify that the data entered into the Electronic Case Report Forms are complete and accurate. After database lock, the investigator will receive copies of the subject data for archiving at the investigational site.
  • Novartis or designated CRO staff review the data entered into the CRFs by investigational staff for completeness and accuracy and instruct the site personnel to make any required corrections or additions. Queries are sent to the investigational site via the EDC system. Designated investigator site staff is required to respond to the query and confirm or correct the data. If the electronic query system is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff who will make the correction to the database. The signed copy of the Data Query Form is kept at the investigator site. Concomitant medications entered into the database will be coded using the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification system. Medical history/current medical conditions and adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology. Laboratory results will be sent electronically to Novartis (or a designated CRO).
  • the safety analysis set will include all subjects that received any study drug.
  • the PK analysis set will include all subjects with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and with no protocol deviations that impact on PK data.
  • the PD analysis set will include all subjects with available PD data and no protocol deviations with relevant impact on PD data.
  • the primary analysis will assess the treatment effect of LIK066 on free T at Day 15.
  • the ratio of Day 15 to baseline free T will be analyzed in an analysis of covariance model with treatment as a categorical factor and baseline free T as a covariate. Additional baseline characteristics that may be predictive of free T may be added to the model as covariates. The logarithm of the ratio and of baseline free T will be applied prior to the analysis.
  • the geometric mean of the ratio to baseline for free T will be estimated from the model for LIK066 and placebo, along with the treatment ratio and the associated p-value and two- sided 90% confidence interval (CI). From these quantities, the following criteria will be assessed:
  • the first criterion addresses with high certainty whether the effect of LIK066 on free T reduction is superior to placebo.
  • the second criterion addresses whether the observed treatment effect of LIK066 on free T reduction is at least 25%.
  • An effect size of 20-25% on hyperandrogenism is considered to be clinically meaningful in PCOS as it correlates with improved ovulation and fertility.
  • Subjects who are deemed to have hormonal evidence of ovulation during the study may be excluded from the primary analysis. Handling of missing values/censoring/discontinuations
  • the primary efficacy analysis will be based on all subjects with an evaluable baseline and Day 15 free T profile and that have no hormonal evidence of ovulation during the study.
  • the change from baseline in free T at Day 15 will be analyzed in an analysis of covariance model of the same form as the one specified for the primary analysis, except no logarithmic transformation will be applied.
  • the least-squares mean change from baseline will be estimated from the model for LIK066 and placebo, along with the treatment difference and the associated p-value and two-sided 90% confidence interval.
  • the secondary variables will be the gonadotropins (LH and FSH), the sex steroids (total testosterone, estradiol, progesterone, DHEAS, DHEA, androstenedione), SHBG, and free androgen index.
  • LH and FSH gonadotropins
  • sex steroids total testosterone, estradiol, progesterone, DHEAS, DHEA, androstenedione
  • SHBG free androgen index
  • free androgen index for LH, FSH, and total testosterone, the average of the three morning fasting concentrations will be additional secondary variables.
  • Each of the secondary variables will be listed by treatment group, subject, and visit/time and summarized by treatment and visit/time.
  • the change from baseline and % change from baseline will also be listed and summarized.
  • the ratio of Day 15 to baseline will be analyzed in an analysis of covariance model with treatment as a categorical factor and baseline as a covariate.
  • the logarithm of the ratio and of baseline will be applied prior to the analysis.
  • the geometric mean of the ratio to baseline will be estimated from the model for LIK066 and placebo, along with the treatment ratio and the associated p-value and two-sided 90% confidence interval.
  • Vital signs All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be provided by treatment and visit/time.
  • ECG data will be listed by treatment group, subject and visit/time, abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time.
  • the number and percentage of subjects with adverse events will be tabulated by body system and preferred term with a breakdown by treatment.
  • a subject with multiple adverse events within a body system is only counted once towards the total of this body system.
  • LIK066 plasma concentration data will be listed by treatment, subject, and visit/sampling time point. Descriptive statistics will be provided by treatment and visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero. Concentrations below LLOQ will be treated as zero in summary statistics and for PK parameter calculations. A geometric mean will not be reported if the dataset includes zero values.
  • PK parameters will be listed by treatment and subject and summarized by treatment.
  • Descriptive statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, and maximum.
  • An exception to this is Tmax where median, minimum, and maximum will be presented.
  • PK and key PD parameters on Day 15 may be explored using a graphical approach.
  • sample size calculation The sample size for this study has been based on a relevant interventional study in a similar population of adults with PCOS.
  • the study reported a decrease in free T of 19% after 7 days of treatment with AZD4901 , a neurokinin B receptor antagonist.
  • the sample size calculation assumes similar baseline characteristics of free T, a 2% reduction in free T in the placebo arm, and a correlation between baseline and Day 14 free T of 0.5. The assumption also is that the true treatment effect of LIK066 is 35% over placebo.

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Abstract

L'invention concerne l'utilisation de LIK066 dans le traitement, la prévention ou le retardement du syndrome des ovaires polykystiques.
PCT/IB2018/053199 2017-05-11 2018-05-08 Traitement du syndrome des ovaires polykystiques Ceased WO2018207099A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2998292A1 (fr) * 2014-09-16 2016-03-23 Sanofi Dérivés de sulfonamide naphtyle en tant que modulateurs de KEAP-1 pour le traitement des diabètes, de l'obésité, de la dyslipidémie et de troubles apparentés

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2998292A1 (fr) * 2014-09-16 2016-03-23 Sanofi Dérivés de sulfonamide naphtyle en tant que modulateurs de KEAP-1 pour le traitement des diabètes, de l'obésité, de la dyslipidémie et de troubles apparentés

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"Handbook of Pharmaceutical Salts, Properties, Selection, and Use", 2002, WILEY-VCH AND VHCA
"Remington's Pharmaceutical Sciences", MACK
ANONYMOUS: "Study of Pharmacodynamics of LIK066 in Overweight and Obese Women With Polycystic Ovary Syndrome - Full Text View - ClinicalTrials.gov", 15 May 2017 (2017-05-15), XP055494451, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/NCT03152591> [retrieved on 20180723] *
DAVID H GELLER ET AL: "State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)", INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY, BIOMED CENTRAL LTD, LONDON, UK, vol. 2011, no. 1, 26 August 2011 (2011-08-26), pages 9, XP021109290, ISSN: 1687-9856, DOI: 10.1186/1687-9856-2011-9 *
KALRA SANJAY: "Sodium-glucose cotransporter 2 inhibition and health benefits: The Robin Hood effect", INDIAN JOURNAL OF ENDOCRINOLOGY AND METABOLISM | PUBLISHED BY WOLTERS KLUWER -MEDKNOW, 1 January 2016 (2016-01-01), XP055494314, Retrieved from the Internet <URL:http://www.ijem.in/temp/IndianJEndocrMetab205725-3529346_094813.pdf> [retrieved on 20180720], DOI: 10.4103/2230-8210.183826 *
NOVARTIS PHARMACEUTICALS: "Effect of LIK066 on Glucose Absorption in Patients With Type 2 Diabetes Mellitus", INTERNET CITATION, 6 February 2015 (2015-02-06), pages 1 - 6, XP009505377, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/study/NCT01915849> [retrieved on 20180515] *
S.M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SD., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
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